The proposed studies are based on the hypothesis that hypertension induces important changes in cerebral artery function. It a rat model of genetic hypertension, experiments with excised pial arteries will be conducted to examine changes in regulatory mechanisms intrinsic to the cerebrovascular wall. A new video-electronic technique will be used in which cerebral arteries ranging in diameter from 25 to 300 mum are cannulated, pressurized and perfused. With this method, the artery experiences a true transmural pressure (static or pulsatile), the endothelium is not damaged, drugs can be selectively applied to the luminal or adventitial surface, and diameter responses of several different-sized vessels to the same stimulus can be measured simultaneously. Aim 1 is to investigate the effects of chronic hypertension on the reactivity of vascular smooth muscle to dynamic alterations in transmural pressure (changes in rate and pulsatile pressure) and to receptor mediated and receptor independent methods of pharmacologic activation. At high transmural pressures, cerebral arteries from hypertensives develop areas of uneven constriction, lending a "sausage-string" appearance to the vessel. The hypothesis will be tested that these segmental differences in tone occur through post-receptor mechanisms in vascular smooth muscle. Aim 2 is to evaluate the impact of chronic hypertension on endothelial permeability and influence on vascular tone. The effect of hypertension on release of and sensitivity to prostacyclin and thromboxane, and to non- prostacyclin endothelial relaxant or constrictor substances will be examined. A chemical technique for endothelial removal in small arteries will be used to determine the extent of endothelial involvement in autoregulatory responses to changes in transmural pressure. In Aim 3 is to study forced dilatation which is thought to be a critical event in the development of hypertensive encephalopathy. Efforts will be directed at evaluating the mechanisms of, and structural damage induced by, forced dilatation in response to sudden pressure elevation in small and large cerebral arteries. These studies will provide important new information on size-receptor differences in cellular regulatory mechanisms operating within the arterial wall, and on how their function is abrogated in hypertension, which is the major risk factor for cerebrovascular disease.